Inflammation represents a major independent risk factor for cardiovascular diseases. One of the prominent[unreadable] features associated with these diseases is the presence of abundant macrophages within the vascular[unreadable] lesions, which contribute to disease development by initiating and sustaining both inflammation and[unreadable] thrombosis and by causing subsequent rupture of the fibrous plaques. During the previous funding period,[unreadable] we studied migration of activated macrophages within an inflammatory environment and identified Mac-1,[unreadable] tPA, fibrin, PAI-1, and LRP as important players in this process. Based on these results, we hypothesize in[unreadable] this application that efficient macrophage migration within inflammatory environments, which functions[unreadable] critically in the resolution of acute inflammation and also during the progression of vascular lesions, depends[unreadable] on cooperation of three physiologically prominent systems (integrins, coagulation, and endocytosis). We[unreadable] propose that inflammation or vascular injury results in the formation of a fibrin-rich matrix. When activated,[unreadable] macrophages adhere to the provisional matrix fibrin that is complexed with the serine protease tPA.[unreadable] Subsequently, tPA is neutralized by its specific inhibitor PAI-1, which in turn enhances binding of the integrinprotease-[unreadable] inhibitor complex to the endocytic receptor LRP, and thus triggers a switch from cell adhesion to[unreadable] cell detachment and promotes receptor internalization. The internalized receptors are then recycled to the[unreadable] cell surface and the next cycle of adhesion, detachment and receptor internalization starts again. Such[unreadable] orderly transitions both spatially and temporally among the individual steps of cell migration lead to efficient[unreadable] macrophage migration. We plan to test this hypothesis using a panel of deficient mice, including Mac-1,[unreadable] fibrinogen, tPA, PAI-1, and LRP. We will also generate specific mutants of Mac-1, tPA, PAI-1, and LRP that[unreadable] are unable to interact with their respective partners and thus will not support the sequential assembly of the[unreadable] above protein complex or macrophage migration. The information obtained from this project will provide[unreadable] detailed mechanistic insights in macrophage migration within an inflammatory milieu and may help us better[unreadable] understand the molecular events that regulate either proper resolution of an acute inflammation under[unreadable] physiological conditions or the development of vascualr lesions within the vessel wall under pathological[unreadable] settings.